This proposal describes a research program which extends our previous work on pain in the human newborn infant by studying pain reactivity to varied stimuli in a developmentally and clinically diverse sample of infants within and beyond the neonatal period. To study pain, we will systematically measure physiologic, behavioral and acoustic parameters of newborn infants in response to invasive, clinically-required beside procedures or parentally-requested circumcision surgery during their hospitalizations. The 250 subjects will include premature and full term, healthy and sick infants, with and without brain injury, with and without assisted mechanical ventilation, who have been recruited for study shortly after admission to a Level I, II or III nursery. Our primary measures include mean heart rate, blood pressure, vagal tone, oxygen saturation, cry fundamental frequency and the presence of a "cry face" expression. Studies will be conducted for all infants in response to a clinically-required heel stick procedure shortly after admission and, subsequently, in response to at least two additional procedures to include a lumbar puncture, intravenous line placement or circumcision surgery and a physical exam. Subjects will be studied during additional clinically-required invasive procedures during hospitalization. To assess the acute and more prolonged effects of pain, we will conduct a randomized controlled trial in healthy, full term infants to examine how anesthesia for circumcision surgery alters response to a post- circumcision heel stick. At six months, a subsample of 100 infants will be studied during a laboratory temperament assessment and a physical exam. Together, these studies will allow us to 1) quantify the influence of neonatal characteristics, perinatal events and stimulus invasiveness on neonatal pain reactivity; 2) construct a stimulus-response gradient of infant pain which can be compared with adult-based models and perceptions of pain; 3) determine whether early reactions to pain predict subsequent reactivity; and 4) quantify the relation between physiologic reactivity and infant temperament. The proposed studies respond directly to the public health need for special pain expertise to be developed for the care of newborn and, especially, premature infants. Special attention is focused on the development of an accurate, multidisciplinary assessment of infant pain and on patient outcome. These studies will generate research data which are directly translatable into clinical decisions at the bedside. The proposed research provides an opportunity to make major advances in our understanding of pain in newborn infants and how best to manage it.